Ahead of Print -Multidrug-Resistant Tuberculosis in Europe, 2010–2011 - Volume 21, Number 3—March 2015 - Emerging Infectious Disease journal - CDC

Ahead of Print -Multidrug-Resistant Tuberculosis in Europe, 2010–2011 - Volume 21, Number 3—March 2015 - Emerging Infectious Disease journal - CDC

Figure. TBNET study sites in the Pan European network for study and clinical management of drug- resistant tuberculosis (TBPAN-NET) project. Stratification is based on the incidence of tuberculosis (TB) reported during 2010–2011,...

Volume 21, Number 3—March 2015

Research

Multidrug-Resistant Tuberculosis in Europe, 2010–2011

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• Methods
• Results
• Discussion
• Suggested Citation

Figures

• Figure

Tables

• Table 1
• Table 2
• Table 3

Technical Appendicies

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Gunar Günther, Frank van Leth, Sofia Alexandru, Neus Altet, Korkut Avsar, Didi Bang, Raisa Barbuta, Graham Bothamley, Ana Ciobanu, Valeriu Crudu, Manfred Davilovits, Martin Dedicoat, Raquel Duarte, Gina Gualano, Heinke Kunst, Wiel de Lange, Vaira Leimane, Cecile Magis-Escurra, Anne-Marie McLaughlin, Inge Muylle, Veronika Polcová, Emanuele Pontali, Christina Popa, Rudolf Rumetshofer, Alena Skrahina, Varvara Solodovnikova, Victor Spinu, Simon Tiberi, Piret Viiklepp, Christoph Lange , and TBNET

Author affiliations: University of Namibia School of Medicine, Windhoek, Namibia (G. Günther, C. Lange);Research Center Borstel, Borstel, Germany (G. Günther, C. Lange); University of Amsterdam, Amsterdam, the Netherlands (F. van Leth); Institute of Phthisiopneumology, Chisinau, Moldova (S. Alexandru, A. Ciubanu, V. Crudu); Hospital Universitari Vall d’Hebron, Barcelona, Spain (N. Altet); Jordi Gol University, Barcelona (N. Altet); Asklepios Klinik Gauting, Gauting, Germany (K. Avsar); Statens Serum Institut, Copenhagen, Denmark (D. Bang); Herlev Hospital, Herlev, Denmark (D. Bang); Balti Municipal Hospital, Balti, Moldova (R. Barbuta);Homerton University Hospital, London, UK (G. Bothamley); National TB Reference Laboratory, Chisinau, Moldova (V. Crudu); Tartu University Lung Hospital, Tartu, Estonia (M. Danilovits); University of Warwick, Coventry, UK (M. Dedicoat); Heart of England Foundation Trust, Birmingham, UK (M. Dedicoat, H. Kunst); Vila Nova de Gaia/Espinho Medical School, Vila Nova de Gaia, Portugal (R. Duarte); Porto University, Porto, Portugal (R. Duarte); National Institute for Infectious Diseases L. Spallanzani, Rome, Italy (G. Gualano); Queen Mary University, London (H. Kunst); University Medical Center Groningen, Groningen, the Netherlands (W. de Lange);Riga East University Hospital, Riga, Latvia (V. Leimane); Radboud University Medical Centre, Nijmegen/Groesbeek, the Netherlands (C. Magis-Escurra); St. James's Hospital, Dublin, Ireland (A.-M. McLaughlin); University Medical Center St. Pieter, Brussels, Belgium (I. Muylle); Thomayer University Hospital, Prague, Czech Republic (V. Polcavá); Galliera Hospital, Genoa, Italy (E. Pontali); Marius-Nasta-Institut, Bucharest, Romania (C. Popa, V. Spinu); Otto Wagner Hospital, Vienna, Austria (R. Rumetshofer); Republican Research and Practical Centre for Pulmonology and Tuberculosis, Minsk, Belarus (A. Skrahina, Varvara Solodovnikova);Azienda Ospedaliera della Valtellina e della Valchiavenna E. Morelli Reference Hospital for MDR and HIV-TB, Sondalo, Italy (S. Tiberi); Barts Health National Health Service Trust, London (S. Tiberi); National Institute for Health Development, Tallinn, Estonia, (P. Viiklepp); Karolinska Institute, Stockholm, Sweden (C. Lange)

Suggested citation for this article

Abstract

Drug-resistant Mycobacterium tuberculosis is challenging elimination of tuberculosis (TB). We evaluated risk factors for TB and levels of second-line drug resistance in M. tuberculosis in patients in Europe with multidrug-resistant (MDR) TB. A total of 380 patients with MDR TB and 376 patients with non–MDR TB were enrolled at 23 centers in 16 countries in Europe during 2010–2011. A total of 52.4% of MDR TB patients had never been treated for TB, which suggests primary transmission of MDR M. tuberculosis. At initiation of treatment for MDR TB, 59.7% of M. tuberculosis strains tested were resistant to pyrazinamide, 51.1% were resistant to ≥1 second-line drug, 26.6% were resistant to second-line injectable drugs, 17.6% were resistant to fluoroquinolones, and 6.8% were extensively drug resistant. Previous treatment for TB was the strongest risk factor for MDR TB. High levels of primary transmission and advanced resistance to second-line drugs characterize MDR TB cases in Europe.

Emergence of drug-resistant tuberculosis (TB) threatens the goal of TB elimination (1). Multidrug-resistant (MDR) TB is defined by in vitro resistance ofMycobacterium tuberculosis to at least both of the 2 most effective drugs for treatment (rifampin and isoniazid). Extensively drug-resistant TB (XDR TB) is defined as MDR TB plus in vitro resistance to at least 1 second-line injectable drug (amikacin, capreomycin, or kanamycin) plus resistance to any of the fluoroquinolones (e.g., ofloxacin, levofloxacin, or moxifloxacin) (2). In the World Health Organization (WHO) European Region, the estimated incidence of patients with MDR TB differs markedly: 1.6 cases/100,000 persons in the 29 European Union/European Economic Area countries and 16.8 cases/100,000 persons in the 24 other countries of the region in 2012 (Technical Appendix[PDF - 147 KB - 6 pages] Table 1) (3). The actual number of patients with MDR TB living in this region may be much higher because a substantial proportion of patients are never screened for drug-resistant TB before starting treatment, partly because of a lack of diagnostic capacity (3).

MDR TB is associated with poor treatment outcomes (1,2,4). The proportion of treatment success in patients with MDR TB was only 54% in an individual patient data metaanalysis of >9,000 patients from 32 observational studies (5). Results from this cohort showed that additional resistance to fluoroquinolones in patients with MDR TB reduced treatment success to 48%; patients with XDR TB were treated successfully in 40% of cases (6), which approached treatment outcomes similar to those of the pre–antimicrobial drug era (4). A recent surveillance report from the EU reported 32.2% treatment success for MDR TB and 19.1% treatment success for XDR TB (7).

Detailed information about characteristics, management, and outcomes of patients with MDR TB in Europe is scarce but essential to inform health policy makers and optimize disease management (8). We compared baseline characteristics and risk factors for patients with MDR TB, as well as availability and results of drug susceptibility testing (DST) for second-line drugs for treatment of TB, in a cohort of patients from 16 countries in Europe with low, intermediate, and high incidence of TB, who had started first-line or second-line TB treatment.

Dr. Günther is a consultant physician and project manager of the TBNET MDR TB cohort at the Research Center Borstel, Borstel, Germany. His primary research interest is drug-resistant tuberculosis.

Acknowledgments

We thank Cordula Ehlers for providing excellent assistance.

Additional contributors from TBNET: Marcel Rowhani (Vienna, Austria); Vera Avchinko, Dzimitry Katovich, Dzimitri Klimuk, Valentina Lobik, Zoya Rohaya, Alexander Shirochyn (Minsk, Belarus); Jana Kotrbova, Martina Vasakova (Prague, Czech Republic); Aase Bengard Andersen (Copenhagen, Denmark); Nelleke Smitsman (Borstel, Germany); Ralf Mütterlein (Parsberg, Germany); Saverio de Lorenzo (Sondalo, Italy); Liga Rusmane (Riga, Latvia); Ana Donica, Ilie Cernenco (Chisinau, Moldavia); Vera Dubceac (Balti, Moldavia); Femke Cuppen, Inge de Guchtenaire (Nijmegen, the Netherlands); Robert Meesters, Mark te Pas, Bram Prins (Amsterdam, the Netherlands); Ana Atunes (Villa Nova de Gaia, Portugal); Dan Gainaru, Elmira Ibraim, Mirela Tigau (Bucharest, Romania); Juan Cayla, Laia Fina, Maria Luiza de Souza Galvao, José Maldonado (Barcelona, Spain).

References

1. World Health Organization. Global tuberculosis report 2013. Geneva: The Organization; 2013.
2. World Health Organization. WHO global task force outlines measures to combat XDR-TB worldwide. 2006 [cited 2014 May 10].http://www.who.int/mediacentre/news/notes/2006/np29/en/
3. European Centre for Disease Prevention and Control/WHO Regional Office for Europe. Tuberculosis surveillance and monitoring in Europe 2014. Stockholm: The Centre; 2014.
4. Grzybowski S, Enarson DA. The fate of cases of pulmonary tuberculosis under various treatment programmes. Bull Int Union Tuberc Lung Dis.1978;53:70–5.
5. Ahuja SD, Ashkin D, Avendano M, Banerjee R, Bauer M, Bayona JN, Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta-analysis of 9,153 patients. PLoS Med. 2012;9:e1001300 . DOIPubMed
6. Falzon D, Gandhi N, Migliori GB, Sotgiu G, Cox HS, Holtz TH, Resistance to fluoroquinolones and second-line injectable drugs: impact on multidrug-resistant TB outcomes. Eur Respir J. 2013;42:156–68. DOIPubMed
7. van der Werf MJ, Kodmön C, Hollo V, Sandgren A, Zucs P. Drug resistance among tuberculosis cases in the European Union and European Economic Area, 2007 to 2012. Euro Surveill. 2014;19:20733 .PubMed
8. van der Werf MJ, Langendam MW, Huitric E, Manissero D. Knowledge of tuberculosis-treatment prescription of health workers: a systematic review. Eur Respir J. 2012;39:1248–55. DOIPubMed
9. Giehl C, Lange C, Duarte R, Bothamley G, Gerlach C, Cirillo DM, TBNET: collaborative research on tuberculosis in Europe. Eur J Microbiol Immunol (Bp). 2012;2:264–74.
10. European Centre for Disease Prevention and Control/WHO Regional Office for Europe. Tuberculosis surveillance and monitoring in Europe 2013. Stockholm: The Centre; 2013.
11. World Health Organization. Definitions and reporting framework for tuberculosis—2013 revision [cited 2014 May 20].http://apps.who.int/iris/bitstream/10665/79199/1/9789241505345_eng.pdf
12. Lange C, Abubakr I, Alfenaar JW, Bothamley G, Caminero JA, Calvarho AC, Management of patients with multidrugresistant/extensively drug-resistant tuberculosis in Europe: a TBNET consensus statement. Eur Respir J. 2014;44:23–63. DOIPubMed
13. Kreuter F, Valliant R. A survey on survey statistics: what is done and can be done in Stata. Stata J. 2007;7:1–21.
14. Lemeshow S, Letenneur L, Dartigues JF, Lafont S, Orgogozo JM, Commenges D. Illustration of analysis taking into account complex survey considerations: the association between wine consumption and dementia in the PAQUID study. Am J Epidemiol. 1998;148:298–306 .DOIPubMed
15. van Leth F, Kalisvaart NA, Erkens CG, Borgdoff MW. Projection of the number of patients with tuberculosis in the Netherlands in 2030. Eur J Public Health. 2009;19:424–7. DOIPubMed
16. World Health Organization. Office for Europe: roadmap to prevent and combat drug-resistant tuberculosis, 2011 [cited 2014 Sep 18].http://www.euro.who.int/en/publications/abstracts/roadmap-to-prevent-and-combat-drug-resistant-tuberculosis
17. Uys PW, Warren R, van Helden PD, Murray M, Victor TC. Potential of rapid diagnosis for controlling drug-susceptible and drug-resistant tuberculosis in communities where Mycobacterium tuberculosis infections are highly prevalent. J Clin Microbiol. 2009;47:1484–90.DOIPubMed
18. van der Werf MJ, Langendam MW, Huitric E, Manissero D. Multidrug resistance after inappropriate tuberculosis treatment: a meta-analysis. Eur Respir J. 2012;39:1511–9. DOIPubMed
19. Skrahina A, Hurevich H, Zalutskaya A, Sahalchyk E, Astrauko A, Hoffner S, Multidrug-resistant tuberculosis in Belarus: the size of the problem and associated risk factors. Bull World Health Organ. 2013;91:36–45. DOIPubMed
20. Royce S, Falzon D, van Weezenbeek C, Dara M, Hyder K, Hopewell P, Multidrug resistance in new tuberculosis patients: burden and implications. Int J Tuberc Lung Dis. 2013;17:511–3. DOIPubMed
21. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis. 2011 update. WHO/HTM/TB/2011.6:1-33 [cited 2014 Nov 13]. http://whqlibdoc.who.int/publications/2011/9789241501583_eng.pdf
22. Dalton T, Cegielski P, Akksilp S, Asencios L, Campos Caoili J, Cho SN, Prevalence of and risk factors for resistance to second-line drugs in people with multidrug-resistant tuberculosis in eight countries: a prospective cohort study. Lancet. 2012;380:1406–17. DOIPubMed
23. Hoffner S. Unexpected high levels of multidrug-resistant tuberculosis present new challenges for tuberculosis control. Lancet. 2012;380:1367–9.DOIPubMed
24. Cegielski JP, Dalton T, Yagui M, Wattanaamornkiet W, Volchenkov GV, Via LE, Extensive drug resistance acquired during treatment of multidrug-resistant tuberculosis. Clin Infect Dis. 2014;59:1049–63. DOIPubMed
25. Van Deun A, Kya Jai Maug A, Halim MA, Kumar Das P, Ranjan Sarker M, Daru P, Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med. 2010;182:684–92. DOIPubMed
26. Singh KP, Brown M, Murphy ME, Gillespie SH. Moxifloxacin for tuberculosis. Lancet Infect Dis. 2012;12:176, author reply 177–8 . DOIPubMed
27. Jacobson KR, Tierney DB, Jeon CY, Mitnick CD, Murray MB. Treatment outcomes among patients with extensively drug-resistant tuberculosis: systematic review and meta-analysis. Clin Infect Dis. 2010;51:6–14. DOIPubMed
28. Kliiman K, Altraja A. Predictors of extensively drug-resistant pulmonary tuberculosis. Ann Intern Med. 2009;150:766–75. DOIPubMed
29. Zhao Y, Xu S, Wang L, Chin DP, Wang S, Jiang G, National survey of drug-resistant tuberculosis in China. N Engl J Med. 2012;366:2161–70.DOIPubMed
30. Hillemann D, Hoffner S, Cirillo D, Drobniewski F, Richter E, Rusch-Gerdes S. First evaluation after implementation of a quality control system for the second line drug susceptibility testing of Mycobacterium tuberculosis joint efforts in low and high incidence countries. PLoS ONE. 2013;8:e76765.DOIPubMed

Figure

• Figure. TBNET study sites in the Pan European network for study and clinical management of drug- resistant tuberculosis (TBPAN-NET) project. Stratification is based on the incidence of tuberculosis (TB) reported during...

Tables

• Table 1. Baseline characteristics of patients with MDR TB in TBNET study in Europe, 2010–2011
• Table 2. Drug resistance profiles for first-line and second-line drugs used for treatment of multidrug-resistant tuberculosis in TBNET study in Europe, 2010–2011
• Table 3. Risk factors for multidrug-resistant tuberculosis in patients in TBNET study in Europe, 2010–2011

Technical Appendix

• . Additional information for TBNET study of multidrug-resistant tuberculosis in Europe, 2010–2011.  147 KB

Suggested citation for this article: Günther G, van Leth F, Alexandru S, Altet N, Avsar K, Bang D, et al. Multidrug-resistant tuberculosis in Europe, 2010–2011. Emerg Infect Dis. 2015 Mar [date cited]. http://dx.doi.org/10.3201/eid2103.141343

DOI: 10.3201/eid2103.141343

1Additional contributors from TBNET are listed at the end of this article.